The addition of oxaliplatin and irinotecan to available first-line therapies makes available multiple combination regimens and increases the complexity of determining the "best" second-line therapy. Patient factors, such as prior therapy and prognostic factors, need to be considered when choosing the appropriate therapy for patients with metastatic colorectal cancer who have progressed on or soon after their first-line therapy. Irinotecan has shown improved survival in patients who had previously failed 5-fluorouracil (5-FU)-based therapy in phase II and III trials. Patients who have failed first-line therapy have benefited from 5-FU, leucovorin, and irinotecan (IFL), 5-FU, leucovorin, and oxaliplatin (FOLFOX), and 5-FU, leucovorin, and irinotecan (FOLFIRI) in the second-line treatment setting. The role of targeted agents is being investigated and preliminary data appear promising. Data from randomized phase III trials using a combination of chemotherapy and bevacizumab or cetuximab are necessary before incorporating these new agents into our routine practice.